Patient safety is our number one priority. Proactive safety strategies thus drive our decision-making and we strive to mitigate risks for all our medicinal products.
Before an active pharmaceutical ingredient (API) is used in humans, we conduct extensive pre-clinical trials that test for aspects such as efficacy and toxicity. After this, the API is tested in humans within the scope of clinical trials that investigate the API's efficacy and adverse effects. The trial results are then used to assess the drug's benefit-risk ratio, weighing the benefits of the treatment against its risks. We create benefit-risk profiles for all our medicinal products to ensure that a positive benefit-risk balance is in place for all medicinal products marketed by us. In 2014, we updated our benefit-risk analysis practice by implementing an improved systematic process.
Information from clinical trials provides an important basis for a drug to be approved by the regulatory authorities. After receiving marketing approval, we continue to conduct benefit-risk evaluations on the drug since the number of patients using it increases exponentially – to thousands or millions worldwide. We thus gain a deeper understanding of the safety profile of our drugs.
At the biopharmaceuticals business, the Global Drug Safety unit is responsible for continuously monitoring the safety profiles of our drugs (pharmacovigilance). Global Drug Safety processes safety information from various sources such as clinical trials, adverse reaction reports and scientific literature in order to ensure up-to-date safety information for patients and their healthcare providers during the entire life cycle of our drugs, from development to the end of marketing authorization.
Pharmacovigilance information is compiled from doctors and patients in all countries in which our medicinal products are marketed. Medical specialists and pharmacovigilance teams ensure that information on adverse effects is correctly compiled, tracked, and communicated. The data for all of our drugs is medically evaluated by the Global Drug Safety functions, who adapts the benefit-risk evaluations as necessary. In line with regulatory requirements, changes to the benefit-risk evaluation and potential safety risks are reported to the responsible authorities, as well as to doctors and patients.
Global Drug Safety at the company's headquarters and the drug safety units within our subsidiaries continuously review changes in the pharmacovigilance regulations worldwide – for products in both the development as well as the marketing phase. New regulations are continuously integrated into our Group-wide processes, thus allowing us to ensure that regulatory requirements and statutory regulations are adhered to. Since the European Medicines Agency (EMA) released its “” (GVP) in 2012, we have reviewed any new or updated GVP Modules and implemented them in our internal pharmacovigilance processes. In 2014, the European Medicines Agency published the new GVP Module on risk mitigation, as well as the revised GVP Modules on Individual Case Report Management and on Periodic Safety Update Report Management. We have integrated the new and revised requirements from these GVP Modules into our processes.
Health authorities regularly conduct pharmacovigilance inspections to review our adherence to regulatory requirements as well as to our own internal drug safety standards. The German Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (the Federal Institute for Vaccines and Biomedicines) - Germany's two pharmaceutical regulatory agencies - conducted a pharmacovigilance inspection on the biopharmaceuticals business Global Drug Safety in February 2015. Conducted on behalf of the European Medicines Agency, this inspection did not yield any critical observations. We are analyzing the non-critical observations that were identified and implementing both corrective as well as preventive measures. In addition to this, we have implemented a worldwide audit program based on the GVP audit module that includes our global activities, as well as affiliates, vendors, and license partners engaged in our pharmacovigilance activities.
The Medical Safety and Ethics Board (MSEB) bears responsibility for drug and medical safety at the biopharmaceuticals business – across the entire life cycle of our drugs, from development to the end of marketing authorization. The Chairman of the MSEB is the Chief Medical Officer (CMO), who also makes the final call on decisions. The board convenes once a month, or on an ad hoc basis as required. In addition to the chairperson, the MSEB consists of experienced physicians, scientists and legal representatives from the biopharmaceuticals business. Its tasks include assessing benefit-risk evaluations, reviewing risk management, and dealing with safety-related communication. Furthermore, it reviews proposals for first-in-man (FIM) clinical studies as well as for updates to the safety warnings on package inserts and labeling. During the life cycle of a medicinal product or medical device, medical, ethical or safety issues that need guidance or a decision from the CMO can be escalated to the MSEB.
In collaboration with other companies as well as organizations from the public sector (e.g. health authorities, academia), the company is involved in (Pharmacoepidemiological research on outcomes of therapeutics by a European consortium), a global research project of the Innovative Medicines Initiative (IMI) launched in 2009. This project aims to further develop and optimize instruments and methods for the benefit-risk evaluation of drugs. The project team established a framework for benefit-risk profiles, which is described in a benefit-risk guide.
Our Quality Training Management standard applies to all employees whose work is related to the quality and safety of a drug or clinical trial. This standard describes how to conduct training workshops and seminars at both the Group level as well as locally within the subsidiaries. Compliance with these requirements is regularly reviewed during the audits of the quality system.
All employees that work in drug development are regularly trained on their drug development expertise and topics related to compliance with ICH, GCP, the respective standard operating procedures, etc. Employee training is provided via a validated learning management system. Depending on their role, a certain training module may be mandatory or optional for the employee. Line managers are responsible for checking whether employees have received all training required by their role.
Good manufacturing practice
In producing pharmaceuticals, quality assurance is a key aspect because deviations can impact patient health and safety. In order to ensure that pharmaceuticals meet the standards set for identity, purity, potency and safety, they must be manufactured according to current Good Manufacturing Practice (). Consequently, as a manufacturer we must have appropriately trained employees as well as suitable facilities, processes and procedures. Compliance with cGMP guidelines is mandatory and monitored by the health authorities.
Product approval and distribution
Merck KGaA, Darmstadt, Germany continuously works to guarantee product availability for its customers. Our requirements for the quality and effectiveness of the distribution process are uniform worldwide. We perform rigorous and frequent checks on our distribution network; these aim to ensure that our partners are adhering to our quality and safety requirements as well as ensure their full compliance with global Good Distribution Practices (GDPs).
The package insert informs patients how to correctly use a product. The package inserts furthermore inform patients about the risks and adverse effects associated with taking the drug. The inserts are regularly reviewed and updated to ensure that they are up to date with the latest information, particularly in terms of safety-relevant information. If the benefit-risk ratio of a product has changed, the MSEB endorses risk mitigation measures. If the risk mitigation measures mean changing the label, this change is then submitted to the labeling decision board. The labeling decision board endorses new labels or label updates in the reference product information (Company Core Data Sheet). The core safety information contained in these reference documents is then implemented in national labeling documents.
In accordance with external requirements, we provide all our drugs with information on safe use and, if applicable, on content - particularly with regard to substances that might produce an environmental or social impact - as well as disposal.